*Prophylactic pectoralis major flap to compensate for increased risk of pharyngocutaneous fistula in laryngectomy patients with low skeletal muscle mass*

In a randomized clinical trial the addition of PMMF as onlay for reinforcement

in low SMM patients will be investigated. Patients who are planned for TL

without PMMC for reconstruction of the mucosal defect will be asked to

participate in this study. After informed consent SMM will be measured using

routinely performed CT or MRI of the head and neck. Patients with low SMM will

be randomized between PMMF reconstruction at the time of TL or not. Incidence

of PCF will be scored for the three groups: patients with low SMM with PMMF as

onlay for reinforcement, patients with low SMM without PMMF and patients

without low SMM. It is hypothesized that the use of PMMF can reduce the PCF

rate to a level similar to TL patients without low SMM.



Skeletal muscle mass measurement

SMM is measured on pre-treatment CT or MRI scans of the head and neck area at

the level of C3 using a previously published method. Whenever possible, CT

imaging was used instead of MRI. In brief, the first slide at the level of C3

when scrolling from caudal to cranial direction to show both transverse

processes and the entire vertebral arc is selected for segmentation of skeletal

muscle (SM) tissue. For CT imaging, skeletal mass (SM) area is defined as the

pixel area within a radiodensity between -29 and +150 Hounsfield Units (HU),

which is specific for SM tissue. For MRI, SM tissue is carefully segmented and

any intramuscular fatty tissue is manually excluded. Segmentation of SM tissue

was manually performed using in house or commercially available software

package SliceOmatic (Tomovision, Canada). An example of SM tissue segmentation

at the level of C3 is shown in Figure 1. After a learning period, the

measurement of SMM requires 5 to 10 minutes per CT scan, and up to 15 minutes

per MRI scan.



From SM area at C3, SM area at the level of L3 is predicted using the

previously published Formula 1. The SM area at L3 is then normalized for height

to calculate the lumbar skeletal muscle index (lumbar SMI), as shown in Formula

2. 12 Low SMM is defined as a lumbar SMI lower than 43.2cm2/m2. This recently

published cut off value was established in a separate cohort of head and neck

cancer patients.



Formula 1:

CSA at L3 (cm2)=27.304+1.363*CSA at C3 (cm2)-0.671*Age (years)+0.640 *Weight

(kg)+26.442 *Sex (Sex=1 for female, 2 for male)



Formula 2:

Lumbar SMI (cm2/m2)=CSA at L3 /length (m2)



In patients who underwent FDG-PET/CT as part of the diagnostic work-up, as a

control of SMM measurement at the level of C3, SMM will also be measured at the

level of L3, which is the most commonly used method in medical literature as a

control of SMM measurement at the level of C3. However, the use of a SMM

measurement at the level of C3 is highly preferable, because of national and

international differences in performing whole body FDG-PET/CT imaging in HNSCC.

All patients are asked to fill out the questionnaires, but performing function

tests will be dependent on the ability in each participating center. At least

in 3 centers the following function tests will be performed: patients with low

SMM will be tested for shoulder and neck disability, swallowing function and

voice quality. Also patients with secondary (for PCF treatment) PM flap will

undergo these tests. Sub analysis will be performed to investigate if there is

a difference in morbidity between prophylactic and secondary PM flap harvest.



Shoulder and neck function

Questionnaires (secondary study parameter)

The shoulder disability questionnaire (SDQ) is a validated pain-related

disability questionnaire including 16 items that describe common conditions

that may induce symptoms in patients with disorders of the shoulder. All items

refer to the preceding 24 hours. Options are *yes*, *no* and *not applicable*.

The *not applicable* category should be used when the condition referred to has

not occurred during the preceding 24 hours. A final score is calculated

dividing the number of *yes* scored items by the total number of items

applicable. And then multiplying the score by 100 results in a final score that

ranges between 0 (no disability) and 100 (all applicable items scored *yes*).

The higher the score, the greater the impairment was. All patients are asked to

fill out the questionnaires for both the left and the right shoulder

separately.

Shoulder function will also be measured with the Shoulder Pain and

Disability Index Dutch Language Version (SPADI-DLV). This questionnaire

consists of 13 items, 5 related to pain and 5 related to function.

Pain of the shoulder is rated on a visual analogue scale (VAS: 0-100

millimeter). Patients are asked to indicate the mean shoulder pain intensity

over the past week.

Patients are also asked if they had experienced stiffness of the shoulder

during the previous week (yes or no).

The Neck Disability Index (NDI) is a questionnaire that captures elements of

neck disability such as pain, work, and headache. The NDI consist of a 10 six

point Likert scale question.



Function tests (part of the main study; performance dependent on the ability in

each participating center)

Active range of motion (AROM) of the shoulder is examined using an inclinometer

according to a standardized protocol. Forward flexion and abduction are

measured in the range of 0-180*. The mean of two sequential measurements is

used for further analysis. To examine endorotation and exorotation an

inclinometer cannot be used because these are combined movements. These will be

measured with a goniometer.

The AROM with the lateroflexion, rotation, extension and flexion of the neck,

is examined using the digital inclinometer.



Swallowing function

Questionnaires (secondary study parameters)

The Dysphagia Severity Scale (DSS) and Dysphagia Quality of Life Scale (DQOL)

are both for laryngetomized patients,non-validated, but rather simple scales to

measure the degree of dysphagia. Patients can indicate on the specific

visualized analogue scale in how they asses swallowing today. The scale ranges

from *not being able to swallow* to * being able to swallow normally* in case

of the DSS. With the DQOL patients will answer to what extend their daily lives

are influenced by the swallowing disorder on the current day. Answers range

from *maximum burden or limitation* to * normal/no burden or limitation.'

The swallowing function in patients after laryngectomy will be measured using

the self-reported patient questionnaire, the Swallow Outcomes After

Laryngectomy (SOAL).[58] This questionnaire is not yet validated for the Dutch

language, but particularly specific for patients with a laryngectomy. This

questionnaire consists of 17 questions about swallowing status and

difficulties. Patients can answer *no*, *a little* or *a lot*. Since we want to

validate the SOAL-questionnaire for the Dutch language, we will use the M.D.

Anderson Dysphagia Inventory (MDADI) to compare the validity. MDADI is a

self-administered questionnaire for head and neck cancer patients and validated

for the Dutch language. The impact of dysphagia on the quality of life is

evaluated. Patients can answer if they *strongly agree*, *agree*, *have no

opinion*, *disagree* or *strongly disagree* with statements about the

swallowing ability and views of the patient.

The Functional Oral Intake Scale (FOIS) for dysphagia is the only investigator

reported outcome questionnaire. It is a standardized 7 point scale to measure

the level of intake (1= complete tube feeding-nothing oral, 7= all intake via

oral rout without restrictions ). The questionnaire is not specifically

designed for laryngectomees, but still gives a good descriptive measure of the

patients.



Function tests (side study; performance dependent on the ability in each

participating center)

To demonstrate the type and extent of an swallowing disorder the Video

Fluoroscopic Swallow Study (VFSS) is the most common used exam. The VFSS gives

detailed information about the swallowing dysfunction. Recommendations

regarding by what method the patient should be nourished can be given

afterwards. This radiographic procedure will be performed only 6 months after

TL.



Voice quality

Questionnaires (secondary study parameter)

Using the Voice Handicap Index (VHI), the psychosocial consequences of voice

disorder will be quantified. This questionnaire is validated for the Dutch

language and based on statements made by people to describe their voice quality

and the effect of their voice on their daily lives. TL - patients can answer if

they *never* , *almost never*, *sometimes*, *almost always* or *always*

experience these statements themselves. The VHI-30 will be used.



Quality index (side study; performance dependent on the ability in each

participating center)

The investigator reported outcome measure will be the Acoustic Voice Quality

Index (AVQI). This index is developed in 2010 and is one of the first indexes

to measure the quality of the voice with a sustained vocalized and continuous

speech. AVQI is a multi-parameter model in which the outcomes of six acoustic

parameters are measured and combined into one objective measure of the severity

of voice quality. Voices of patients will be recorded postoperatively dependent

on the ability in each participating center.



Quality of Life (secondary study parameters)

The following questionnaires will be used to measure QoL: EORTC QLQ-C30,

EORTC-QLQ-H&N35, specific for head and neck cancer patients and EQ-5D-5L. The

EORTC-QLQ is designed to be cancer-specific, multidimensional in structure,

appropriate for self-administration and applicable across a range of cultural

settings. Dutch reference values are available. The EQ-5D is a standardized

instrument can be used as a quantitative measure of health outcome that can be

used in a wide range of health conditions and treatments, and reflects the

patient*s own judgement. Questionnaires are asked to fill out before and 6

months after laryngectomy. The EQ-5D-5L will be filled out 3 months after TL

also.



Patients* experience (secondary study parameter)

Patients* experience with the needed rehabilitation of shoulder and neck

function, swallowing function and voice quality related to provided information

and therapy will be explored by qualitative research with semi-structures

interviews based on a interview guide with a topic list. Questions will focus

on patients* experience with the provided information, content of the needed

therapy related to physical functioning like neck and shoulder problems,

swallowing and speech quality. Semi-structured interviews will be analyzed by

two researchers using thematic descriptive analyses. Data coding will be done

by open, axial and selective coding and will be supported by the software

package NVivo.



Cost-effectiven